Revealing the Central Mechanism of Acupuncture for Primary Dysmenorrhea Based on Neuroimaging: A Narrative Review

Objective The central mechanism of acupuncture for primary dysmenorrhea was explored by summarizing the changes in different regional networks of the brain induced by acupuncture stimulation by analyzing the existing studies. Methods The original studies were collected and selected from three English databases such as PubMed and four Chinese databases as China Knowledge Network (CNKI). The main keyword clusters are neuroimaging, acupuncture, and primary dysmenorrhea. Results The literature review yielded 130 possibly qualified studies, and 23 articles fulfilled the criteria for inclusion. Regarding the type of acupuncture studies, 6 moxibustion studies and 17 manual acupuncture studies for primary dysmenorrhea were included. Based on functional magnetic resonance imaging (fMRI), perfusion-weighted imaging (PWI), and positron emission tomography-computer tomography techniques (PET-CT), one or more analysis methods such as amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC), and independent components analysis (ICA) were used. The results are summarized. To summarize the high-frequency brain area alterations observed in patients with acupuncture-induced primary dysmenorrhea were the anterior cingulate gyrus, thalamus, insula, precentral gyrus, middle frontal gyrus, postcentral gyrus, putamen, and cerebellum. Conclusion The results suggest that the mechanism of acupuncture in the treatment of primary dysmenorrhea is the involvement of networks regulating different areas of the brain in the analgesic effects of acupuncture. The brain regions involved in primary dysmenorrhea acupuncture analgesia were mainly located in the pain matrix, default mode network, salience network, and limbic system.


Introduction
Primary dysmenorrhea (PD) is defned as dysmenorrhea without organic disease of the reproductive organs and accounts for more than 90% of the incidence of dysmenorrhea [1]. Approximately 45% to 90% of women experience dysmenorrhea [2]. Between 10% to 25% sufer from severe dysmenorrhea, which seriously afects the quality of life of patients [3]. Existing studies suggest that the pathogenesis of dysmenorrhea is due to elevated secretion of Prostaglandin F2a (PGF2α) and Prostaglandin E2 (PGE2) causing contraction of uterine vessels and muscles, increased uterine activity, excessive contracture resulting in reduced blood fow and tissue ischemia, and hypoxia causing pain [2,4]. Current treatments for dysmenorrhea include pharmacotherapy and complementary drug therapy. Te common pharmacological therapies are oral nonsteroidal antiinfammatory drugs (NSAIDs) and birth control pills. However, long-term use of drugs can produce many gastrointestinal side efects. In supplemental medicine, herbs, yoga, relaxation, psychotherapy, massage, and acupuncture are used for healing [5].
Acupuncture is commonly used as an alternative treatment for PD because of its efcacy and safety [6]. Available studies have indicated that acupuncture treats PD by regulating endocrine and analgesic substances, modulating immune-infammatory responses, improving uterine blood fow, and reducing oxidative stress [7].
Tere are more neuroimaging research methods, which are commonly used to study functional brain connectivity, metabolite content, neuroreceptor distribution, and brain area activation, mainly fMRI and PET. fMRI is a blood oxygenation level-dependent functional brain imaging, which is based on the principle of measuring changes in the degree of oxygenation in local cerebral blood fow, which indirectly refects the operational activities of brain regions [8]. Tere are several analysis methods for fMRI, and the commonly used analysis methods are ALFF/FC/ReHo. ALFF measures the amplitude of fuctuations at low frequencies when the nerve activity is stationary [9,10]. FC reveals the exchange of functional information between diferent brain regions at the anatomical level [11,12]. ReHo detects localized regional functional synchronization in the brain, responding to the state of neural activity [13]. PET imaging is a nuclear medicine imaging technique in which a radioactive tracer is usually injected intravenously, followed by observation of the distribution and quantifcation of the target substance. PET imaging is commonly used to detect cerebral blood fow, assess functional indicators such as glucose metabolism and oxygen consumption, and quantify diferences in the density of proteins such as receptors, transport proteins, and enzymes.
Neuroimaging has been widely used to observe brain alterations in patients with dysmenorrhea, and studies have shown that patients with PD have a particular alteration in the density of functional connectivity in brain networks associated with pain [14,15]. Some studies have also attempted to clarify the targets of the action of acupuncture for PD through neuroimaging [16]. Or use neuroimaging for the prediction of the onset of dysmenorrhea [17][18][19].
Tere is a lack of reviews to summarize the central mechanisms of acupuncture for PD and to assess the brain alterations in people with PD under acupuncture intervention. Tis review aims to further clarify the central mechanism of acupuncture for PD by systematically reviewing 25 studies on neuroimaging of acupuncture for PD, analyzing the fndings and methodological issues and changes in brain networks, and providing a reference for future research directions [5].  Table 5). Te previous was screened by two reviewers and diferences were settled by consulting the third reviewer.

Results
Tis review includes 23 original articles from a total of 25 studies.
In 15 studies, the Visual Analog Scale (VAS) was applied to evaluate pain levels in women with PD [17, 22-30, 35, 40-43] and further 3 studies used the numerical pain intensity rating (NRS) to assess pain intensity in PD [34,39]. 2 studies used the McGill Pain Questionnaire (MPQ) and the pain rating index (PRI) as scales to assess pain [32,33]. It is worth mentioning that 1 study used the present pain intensity (PPI) as an assessment indicator [33]. In addition, for the status of PD, 4 studies assessed patient symptoms on the Cox Menstrual Symptom Scale (CMSS) [22,25,35,42] and 6 studies assessed patient psychological status using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) [17,22,25,26,36]. State-Trait Anxiety Inventory (SATI) and Beck Depression Inventory-II (BDI-II) have also been used to assess psychological conditions [32,33]. 2 studies used the inclusion of hormonal indicators to assess the efect of acupuncture on patient hormone levels ( Figure 1(f)) [32,33].
Supplementary Table 4 shows the brain activation of acupuncture for PD. Figure 2 depicts the most commonly encountered brain regions.

Discussion
Tis review summarizes the high-frequency brain areas of PD treated by acupuncture through the analysis of the previously mentioned studies and provides a reference for further research on the central mechanism and visual analysis of acupuncture for PD.

Brain Alterations of PD Patients. 4 of the studies in this
review referred to diferences between the brains of dysmenorrheic patients and healthy individuals and found that dysmenorrheic patients exhibited altered brain function. Functional changes were usually manifested by decreased functional connectivity in the medial sensorimotor area, dorsolateral prefrontal, thalamus, insula, and postcentral gyrus, and increased functional connectivity in the medial orbitofrontal and hippocampus [22,27]. Te brain regions with abnormal alterations in ReHo values mainly involved the pain modulation network and the default network [36]. On brain glucose metabolism, brain areas associated with pain showed enhancement, such as the prefrontal, dorsolateral prefrontal, anterior cingulate gyrus, frst somatosensory area, supplementary motor area, and frst somatosensory area, and areas associated with emotion showed attenuation, such as temporal lobe, insula, caudate nucleus, hippocampal gyrus, corpus callosum, and hypothalamus [39]. Tese studies have laid the foundation for an in-depth study of the central mechanisms of acupuncture for PD.

Similarities and Diferences in Brain Alterations in Patients with PD under the Efects of Acupuncture and
Moxibustion. For PD, the number of acupuncture studies is much more than that of moxibustion. In terms of brain alterations in patients with PD, both acupuncture and moxibustion have been shown to activate analgesia-related brain regions to exert analgesic efects. In comparison to moxibustion, acupuncture studies also found that the activation of the nociceptive modulation system in the brain also activated the limbic system associated with emotion and pain perception [24,25,30,41]. Moreover, research has reported that sham acupuncture activates nociceptive and afective brain areas in the retention state, suggesting the presence of a placebo efect of sham acupuncture [30]. Tis is not reported in moxibustion-related studies.

Brain Alterations in Patients with PD under Acupuncture
Infection. In this review, 4 studies have demonstrated a decrease in glucose metabolism in the cerebral cortex and an increase in glucose metabolism in the limbic system in PD patients compared to healthy individuals [23,34,39]. Furthermore, from the perspective of analgesic mechanisms, verum and sham acupuncture modulate the perception of injurious input in PD patients by reducing cerebral blood fow through diferent brain response patterns [32]. In terms of functional connectivity, 4 reports indicated that the analgesic infuence was achieved by activating the nociceptive modulation system in the brain during the postneedling efect. At the same time, the limbic system associated with pain perception was activated [24,25,30,41]. Tis suggests that the central mechanism of acupuncture for PD may be mediated through the activation of the nociceptive modulation system and the cognitive-related limbic system.

Brain Network Alterations in Patients with PD under
Acupuncture Infection. Acupuncture moderates a broadly located network of brain regions, and in this review, acupuncture of brain regions with high-frequency alterations in PD primarily included the anterior cingulate gyrus, hippocampus, thalamus, precuneus, insula, precentral gyrus, middle frontal gyrus, postcentral gyrus, middle temporal gyrus, putamen, and cerebellum as the main brain regions reported. Tey are mainly distributed in the pain matrix, default mode network (DMN), salience network, and limbic system. Te anterior cingulate gyrus is not just an integral component of the "pain matrix" but also a critical area of the salience network and limbic system. Te anterior cingulate cortex is engaged in analgesic regulation, pain memory, and emotional processing [45,46]. Te thalamus is an important relay station for transmitting injurious information to the cerebral cortex and an essential part of pain regulation [47,48]. Notably, the precuneus plays an essential role in the DMN. Some researchers have found that reduced gray matter volume in the precuneus suggests increased thermal pain sensitivity [49]. However, this phenomenon is not present in every region of the pain matrix. Te insula, as an essential node of the salience network as well as the pain matrix, improves individual brain-based pain sensitivity and increases thresholds for human pain, and is an important part of the brain involved in processing pain [50][51][52]. Te cerebellum is commonly thought to be associated with movement, and the cerebellum supports experimental pain and chronic pain processing with its complex sensory, emotional, and neurocognitive aspects [53,54].

Pain Matrix Involved in the Brain Response to PD
Acupuncture. Te integrated study showed that regions of the pain matrix, which consist of the thalamus, precentral gyrus, anterior cingulate gyrus, insula, middle frontal gyrus, postcentral gyrus, and putamen, were involved in the brain response to acupuncture for PD (Figure 2 red dashed line). Activation of the pain matrix was related to the intensity of perceived pain within as well as between individuals [55]. Related studies suggested that matrix stimulation may be an efective method for reducing acute pain, therapeutic intervention with minimal side efects, and in the future, able to expand our pain management options for treating acute pain [56]. Tis review, through the modulatory efects of acupuncture on PD involving key parts of the pain matrix, suggested that acupuncture may work to treat PD by activating the pain matrix.

Default Mode Network Involved in the Brain Response
to Acupuncture in PD. Te hippocampus, precuneus, and middle temporal gyrus are an important portion of the DMN system components involved in the brain response to acupuncture for PD (yellow dashed line in Figure 2). Te DMN is associated with aspects of pain intensity, negative afect, or pain rumination. Related studies suggest that functional or structural abnormalities in relevant areas of the DMN may be related to central mechanisms of PD occurrence [57][58][59]. Terefore, acupuncture may have a therapeutic efect on PD by adjusting the distribution area of DMN.

Salience Network Involved in Acupuncture Brain Response in PD.
Te anterior cingulate gyrus is the most mentioned brain region most mentioned in acupuncture for PD, and together with the insula, it is an important part of the salience network (green dashed line in Figure 2). Interestingly, studies showed that the salience network may be able to predict the onset of menstrual pain [17,60]. It is predicted that the activity of the salience network could be monitored in the future to predict the onset of PD, and thus allow for precise acupuncture treatment of patients with PD.

Te Limbic System is Involved in the Brain
Response to PD Acupuncture. In this review, the anterior cingulate gyrus, hippocampus, and putamen were high-frequency brain areas in the limbic system engaged in acupuncture for PD (blue dashed line in Figure 2). Te limbic system is thought to be the system that processes motivational-emotional aspects, cognitive-evaluative aspects, and pain memory while mediating the analgesic efects of acupuncture [61,62]. Tis suggests that the limbic system may regulate PD by modulating the function of corticolimbic brain regions involved in behavioral and emotional responses.

4.5.
Limitations of the Study Design of Acupuncture Neuroimaging for PD. First, there is a dearth of studies exploring changes in the luteal phase of the brain concerning the timing of imaging acquisition. Can early intervention during the luteal phase, when peak estrogen promotes higher endometrial production of PGE2 relative to PGF2α in the premenstrual phase, alleviates dysmenorrhea if performed during the luteal phase? Brain dynamics are regulated by rhythmic variations in the concentration of female sex hormones throughout the menstrual cycle [63,64]. Te use of acupuncture stimulation during diferent phases of the menstrual cycle may bring about diferent changes in the brain that should be fully explored.
Second, the quality of life of PD patients should be focused on in the included studies by including relevant scales for evaluation. Pain is an unpleasant sensory and emotional experience [65]. Moreover, sex hormones were thought to be involved in modulating pain [66][67][68]. Terefore, PD should be viewed holistically, incorporating psychological, sex hormone levels, and quality of life scores.
Finally, most of the included studies used a single neuroimaging detection technique and a single analysis method. In the future, multiple neuroimaging techniques can be applied to detect dynamic brain activity in PD treated with acupuncture, and multimodal data analysis methods can be explored to gain fuller insight into the structural and functional changes in the brain brought about by PD treated with acupuncture.

Conclusion
Te central mechanism of acupuncture for PD may be achieved by stimulation causing alterations in brain function and changes in diferent regional networks that activate the associated nociceptive and nociceptive cognitive systems. However, there is a need to continue to investigate the infuence of acupuncture on brain alterations in PD patients during diferent phases of the menstrual cycle, and the infuence of acupuncture on sex hormones and brain alterations in PD patients. Meanwhile, combining multiple imaging techniques and multiple data processing methods may become a novel direction to study the central mechanism of acupuncture for PD in the future.

Data Availability
Te raw data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Benlu Chen and Qin Guo contributed equally to this work. Quanai Zhang designed the study. Benlu Chen, Qiwen Zhang, and Qin Guo performed the data extraction. Qin Guo, Benlu Chen, and Zhong Di discussed the consequences and the writing of the article. Quanai Zhang revised the draft. All authors have read and approved the publication of the fnal manuscript.  Figure 1. Te basic information of included studies. Figure 2. Te most commonly encountered brain regions. (Supplementary Materials)